Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221102519.doi: 10.1177/09603271221102519. (IF2.903)

Neurotoxic 18-kDa apolipoprotein E fragment production contributes to anesthetic sevoflurane-induced tau phosphorylation and neuroinflammation in vitro

Yang Yu  1   2 M Yang  3 X Zhuang  1   2 J Pan  1   2 J Feng  1   2 J Yu  1   2 Yonghao Yu  1   2

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Abstract

Anesthesia may induce neuronal tau phosphorylation and neurotoxicity in the developing brain. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and injury repair, whereas its 18-kDa fragments are reported to induce neurodegeneration and neuroinflammation in Alzheimer’s disease patients. We aimed to test the hypothesis that differences in 18-kDa ApoE fragment levels, but not full-length ApoE, in primary neurons contribute to differences in tau phosphorylation and neuroinflammation with or without sevoflurane administration. Neurons extracted from wild-type (WT), ApoE knockout (ApoE-KO), and ApoE ε3-and ε2-targeted replacement (ApoE ε3, ApoE ε2) mice were divided into control and sevoflurane groups. Neurons in the sevoflurane group were treated with 21% O2, 5% CO2, and 4.1% sevoflurane, whereas those in the control group were treated with 21% O2 and 5% CO2 only on day 5 of neuronal culture. ApoE mRNA, full-length ApoE, 18-kDa ApoE fragments, Tau-PS202/PT205 (AT8), Tau-PSer396/404 (PHF1), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 and IL-1β levels were measured. The data showed that sevoflurane-induced AT8 and PHF1 increases, and TNF-α, IL-6, and IL-1β increases in WT or ApoE ε3 neurons (both expressing full-length and 18-kDa fragmented ApoE) could be mitigated in ApoE ε2 (only expressing full-length ApoE), but not in ApoE-KO neurons, indicating that differences in 18-kDa ApoE fragments, but not full-length ApoE, in primary mouse neurons contributed to differences in tau phosphorylation and neuroinflammation with or without 4.1% sevoflurane administration.

Keywords: Sevoflurane; apolipoprotein E-targeted replacement mice; neuroinflammation; neuron; tau phosphorylation.

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